Bacterial resistance, contrary to popular belief, does not just result from an overuse of antibiotics. Bacteria can become resistant when they become dormant. All bacteria have this defense mechanism. Researchers have discovered that oxygen can make dormant bacteria active again so they become responsive to antibiotics and help counteract their resistance.
The discovery was released by scientists belonging to Penn State University, today in the journal Nature Communications.
In their search for treatments that help fight resistance most effectively, the researchers discovered the first oxygen-sensitive toxin-antitoxin system. Bacteria that develop a protective layer of muci and stick together, known as biofilm, are hard to fight as they react to environmental stimuli, secrete a toxin and become dormant. They become resistant because antibiotics fight bacteria that are active, not dormant.
An example of a bacterium that becomes dormant lives in the gastrointestinal tract. Bile, which is a liquid substance that breaks fats into fatty acids, is produced by liver and is stored in gall bladder, when released in the gastrointestinal tract helps kill these bacteria, but some bacteria release a self-toxin that makes them dormant.
When the bile is “washed away”, the bacteria are able to release another protein that eradicates the inhibitor protein and they come out of their dormant state. These toxin-antitoxin systems are innate in bacteria and serve as a defense mechanism against several different external and environmental stimuli.
Thomas K Wood, professor of chemical engineering and holder of the Biotechnology Endowed Chair, Penn State, had this to say regarding the findings, “Antibiotics can only kill bacteria when they are actively growing and dividing. But, environmental stress factors often turn on a bacterial mechanism that creates a toxin that makes the cell dormant and therefore antibiotic resistant.”
This is a remarkable study as it is the first time that a team of scientists was able to identify a toxin-antitoxin system in a biofilm, and the first oxygen dependent toxin-antitoxin system. This discovery was made at the Biomolecular NMR Laboratory at the University of Barcelona, Spain.
The researchers found that the E. coli bacterium’s toxin-antitoxin system had molecular structures that were porous enough to let oxygen molecules pass through. The E. coli toxin-antitoxin system is made up of Hha and TomB proteins, where Hha molecule serves as the toxin while TomB molecule is the antitoxin.
The researchers added that unlike other toxin-antitoxin molecular pairs, in which toxin molecule makes the bacteria wake up while antitoxin makes the bacteria dormant, Hha and TomB pairing needs oxygen in the presence of the antitoxin to oxidize the toxin and wake the bacteria from an inactive dormant state.
Dr Wood added that if scientists are able to understand how bacteria act and respond at a molecular level, scientists will be able to create better antibiotic drugs. He added that in order to do so, fully understanding bacteria’s toxin-antitoxin system is crucial and will better explain how bacteria resist antibiotic attack.
Antibodies or antibiotics can easily target bacteria that are active and mobile, but naturally bacteria that create biofilms and protective layers are tougher to kill. In the case of tuberculosis, bacteria have as many as 88 different toxin options which they can utilize in response to environmental stimuli. This is one of the reasons why patients suffering from tuberculosis need to keep taking antibiotic course for months or years to completely get rid of bacterial invasion from the body.
Biofilms play a vital role in approximately 80% of all human infections and are one of the major factors how bacteria fend off antibiotics. That’s the reason why antibiotic resistance has become a global crisis.
The researchers have noted that according to their estimates, as little as 10% oxygen is ample enough to wake up the bacteria out of a dormant state but when the bacteria are engulfed in a biofilm, the problem becomes far more complex. The bacteria that is surrounding the edges of the biofilm can be easily exposed to oxygen but those that are deeply immersed in the biofilm, oxygen molecules do not affect them. Luckily, the cellular channels that stem in the bacterial biofilm allow the oxygen to pass through into the biofilm, activate the bacteria and disintegrate the biofilm.
The researchers suggest that this type of toxin, one that is oxygen-dependent, could become the target for antibacterial treatments to inhibit the formation of biofilms.
Bacteria develop antibiotic resistance in two ways. Many acquire mutations in their own genomes that allow them to withstand antibiotics, although that ability can’t be shared with pathogens outside their own family. The other way is when the superbug reproduces by manipulating plasmids.
Microorganisms develop resistance when they replicate and exchange genes in between them. However, prescribing antibiotics for the smallest of infections and over-prescriptions by many medical professionals over the years may also have been a reason for microorganisms to develop such hard resistance.
The Centers for Disease Control and Prevention (CDC) has estimated more than 2 million people contract infections from pathogens with antimicrobial resistance, which leads to more than 23,000 deaths every year. Although antibiotics are also one of the most prescribed drugs used for lifesaving conditions in the US, 50% of the time the drugs are given to patients unnecessarily.
Antimicrobial resistance can be developed in microorganisms such as bacteria, fungi, virus, parasites and all microbes which are pathogenic in nature. Even common infections like flu, pneumonia, urinary tract infections etc can become lethal. Other infections of increasing concern all over the world are caused by bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) or multidrug-resistant Gram-negative bacteria.
Given the high risk factor of getting infected, proper measures are needed and quick. There have been numerous efforts by several government agencies. The National Antimicrobial Resistance Monitoring System for Enteric Bacteria (NARMS) is working to keep an eye on the changes in the antimicrobial susceptibility of certain enteric (intestinal) bacteria found in ill people, retail meats and food animals in the United States.
Fortunately for us, if similar medical breakthroughs are continued to be made, antimicrobial resistance will be a thing of the past.